EP0711134B1 - Medikament zum schutz vor neurologischen schäden - Google Patents

Medikament zum schutz vor neurologischen schäden Download PDF

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Publication number
EP0711134B1
EP0711134B1 EP94925157A EP94925157A EP0711134B1 EP 0711134 B1 EP0711134 B1 EP 0711134B1 EP 94925157 A EP94925157 A EP 94925157A EP 94925157 A EP94925157 A EP 94925157A EP 0711134 B1 EP0711134 B1 EP 0711134B1
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EP
European Patent Office
Prior art keywords
dmso
fdp
composition
fructose
diphosphate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP94925157A
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English (en)
French (fr)
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EP0711134A1 (de
EP0711134A4 (de
Inventor
Jack De La Torre
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TORRE JACK DE
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TORRE JACK DE
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Publication date
Application filed by TORRE JACK DE filed Critical TORRE JACK DE
Publication of EP0711134A1 publication Critical patent/EP0711134A1/de
Publication of EP0711134A4 publication Critical patent/EP0711134A4/de
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Publication of EP0711134B1 publication Critical patent/EP0711134B1/de
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S424/00—Drug, bio-affecting and body treating compositions
    • Y10S424/15—Suppositories

Definitions

  • This invention relates to a method of protection from and treatment of neurological damage in mammals by administration of dimethylsulfoxide (DMSO) in combination with fructose 1,6-diphosphate (FDP).
  • DMSO dimethylsulfoxide
  • FDP fructose 1,6-diphosphate
  • ischemia and increased intracranial pressure are associated with many assaults on the brain, including severe head injury, thrombosis, and cerebral hemorrhage. Since the brain has limited reserves of high energy adenyl nucleotides, any condition that results in cerebral ischemia or hypoxia can impair aerobic oxidative metabolism and development of anaerobic glycolysis. Head injury or severe hypoxia can also lead to production of injurious amounts of lactic acid.
  • phosphofructokinase (PFK) the rate-limiting enzyme responsible for the conversion of fructose-6 phosphate to fructose 1,6-diphosphate (FDP)
  • FDP fructose 1,6-diphosphate
  • the resulting condition is one of rapid decline of intracellular adenosine triphosphate (ATP), the major source of cellular energy.
  • ATP adenosine triphosphate
  • Deterioration of the cerebral energy state can also result in the loss of intracellular K + while promoting intracellular free Ca 2+ during depolarization of the neuronal membrane.
  • Experimental evidence has implicated intracellular Ca 2+ accumulation to a chain of biochemical events leading to irreversible neuronal death. Those events include the uncoupling of oxidative phosphorylation, activation of intracellular enzymes and generation of cell-damaging hydroxyl or oxygen free radicals.
  • FDP intravenous FDP can improve electrical brain activity and protect cerebral neurons from damage following ischemic injury in rabbits.
  • a number of studies indicate that FDP is useful in improving brain metabolism following ischemia and hypoglycemic coma, ostensibly by increasing intracellular ATP levels and preventing intracellular Ca 2+ accumulation.
  • FDP appears useful in cardiogenic shock, intestinal ischemia, myocardial infarction or ischemia, renal ischemia, hypoglycemic coma, acute respiratory distress syndrome, liver ischemia and injury, hemorrhagic shock, peritonitis, cardiomyopathy, cardiac arrhythmias and doxorubicin-induced cardiotoxicity.
  • FDP appears as an ideal agent to increase energy production during anaerobic glycolysis and to reduce the formation of oxygen radicals.
  • FDP is a phosphorylated sugar, it crosses the blood-brain barrier and enters the neurons. Theoretically, one mole of FDP yields four moles of ATP whereas one mole of glucose yields only two moles of ATP.
  • large quantities of the compound must be administered.
  • FDP has also been shown beneficial in patients with traumatic shock following spinal cord injury, gun-shot wounds to the neck, chest and abdomen, head injury, and duodenal rupture.
  • DMSO dimethyl sulfoxide
  • DMSO has been shown in numerous experimental studies to reduce intracranial pressure elevation, inhibit platelet aggregation, reduce edema after focal brain ischemia, increase survival after stroke and gun-shot wound to the head. Additionally, it has been reported that DMSO can protect glial cells against sonic damage, increase cerebral and spinal cord blood flow following trauma or ischemia, protect tissue from radiation and cold-induced damage, prevent ischemic damage to the kidney, intestines and brain, improve neurologic outcome after spinal and head trauma and inhibit platelet aggregation in obstructed coronary vessels.
  • DMSO can improve end-stage acute respiratory distress syndrome and, when given to patients intravenously, can reduce intracranial pressure following severe closed head injury, increase cerebral blood flow following cerebral hemorrhage, reduce amyloid deposition in patients with primary amyloidosis, and improve mitochondrial function and energy metabolism partly due to DMSO's action as a free radical scavenger.
  • DMSO has been shown useful in the treatment of reflex sympathetic dystrophy secondary to inflammatory reactions.
  • DMSO is reported to have important biological activity in reducing conduction of painful stimuli through C-fibers and may have anti-carcinogenic, anti-viral action.
  • compositions of matter which may conveniently be used in treatment of hypoxia/ischemia, including hypoxia/ischemia arising from trauma.
  • DMSO dimethyl sulfoxide
  • FDP fructose 1,6-diphosphate
  • FDP is stable at room temperature in its crystalline form, including its salts, for several months and for several days once it is in solution.
  • mouse head injury model used in this study is a standard used in pharmaceutical drug testing of potentially useful compounds in severe brain concussive injury.
  • each mouse was tested for sensory deficits by pinching the fore and hind limb toes with a fine forceps. Each mouse was then grasped by the tail and its front or rear paws were allowed to come in contact with a taut string 60 centimeters long suspended between two metal stands 40 cm above a padded table. The tail was then released and the mouse's ability to grasp and hold on to the string for 90 seconds was tested. The length of time each mouse held on to the string (grip test) was then recorded as the latency in seconds and group means were determined at the end of each time point for 1 or 2 hours following the trauma. Each mouse was placed on the string only once for each test period.
  • GROUP GRIP TEST 1 HOUR GRIP TEST: 2 HOURS DMSO 7 3 DMSO 18 15 DMSO 3 4 DMSO 8 5 DMSO 30 60 DMSO 10 14 MEAN 12.6 16.8 GROUP GRIP TEST: 1 HOUR GRIP TEST: 2 HOURS FDP 30 27 FDP 10 12 FDP 2 1 FDP 2 2 FDP 4 24 FDP 16 22 MEAN 10.6 14.6 GROUP GRIP TEST: 1 HOUR GRIP TEST: 2 HOURS DMSO:FDP 72 84 DMSO:FDP 60 76 DMSO:FDP 90 90 DMSO:FDP 90 90 DMSO:FDP 90 DMSO:FDP 90 86 DMSO:FDP 56 90 MEAN 76.3 86.5 GROUP GRIP TEST: 1 HOUR GRIP TEST: 2 HOURS DMSO 7 3 DMSO 18 15 DMSO 3 4 DMSO 8 5 DMSO 30 60 DMSO 10 14 MEAN 12.6 16.8 GROUP GRIP TEST: 1
  • mice were killed by decapitation 3 hours after the initial head injury and the brains were processed for Palmgren silver impregnation stain.
  • Four micron sections were taken every 100 ⁇ m beginning at the center of the lesion site and proceeding in an antero-posterior direction to the site of trauma.
  • CA1 hippocampal region and fronto-parietal cortex were used for morphometry.
  • the hippocampal region was chosen for morphometry even though it was not directly below the site of trauma because this region is highly vulnerable to brain ischemia and to cerebral swelling following trauma and also because the hippocampus has been linked to learning and memory, functions which are often affected after severe brain trauma.
  • Frontoparietal cortical neurons were evaluated because of their proximity to the lesion site and because damage to this region was relatively consistent among the experimental and non-treated group.
  • Neuronal counts of the fronto-parietal cortex and CA1 region were made by averaging the number of damaged/total neurons from each side of the hippocampus or parietal cortex from five representative sections. Group means were obtained for each treatment and those values were compared to vehicle non-treated controls.
  • Morphometric data was analyzed using a digitizing screen connected to a Jandel program which computed means, sum, standard deviation and standard error.
  • compositions of the invention may be used to treat other disease conditions arising on account of ischemia and hypoxia.
  • diseases include, in addition to closed head injury, any condition that will cause cerebral ischemia/hypoxia or increase intracranial pressure such as stroke, arachnoidal cysts, neoplasms, hydrocephalus, tuberculous meningitis, meningocele, pseudo-tumor cerebri, lead encephalopathy, gun-shot wounds, acquired immunodeficiency syndrome (AIDS), Reye's syndrome, and meningitis (including bacterial, fungal and viral meningitis.)
  • the compositions may also be used to treat other disease conditions that cause ischemia or hypoxia, including myocardial insufficiency, brain edema, tumors, vascular malformations, hemorrhagic shock, cardiogenic shock, traumatic brain coma, spinal cord injury, spinal tumor, syringomyelia.
  • compositions of the invention can also be used in treatment of cerebral energy-related disorders including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, adrenoleukodystrophy, dementia pugilistica, Huntington's chorea, multi-infarct dementia, Pick's disease, hepatic encephalitis and kernicterus.
  • neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, adrenoleukodystrophy, dementia pugilistica, Huntington's chorea, multi-infarct dementia, Pick's disease, hepatic encephalitis and kernicterus.
  • the patient was admitted for a severe head injury with brain tissue extruding from the wound.
  • a solution containing 28% DMSO and 10% FDP made with 5% dextrose in water was given in three divided doses to provide a total dosage of 200mg/Kg/day for 4 days.
  • the patient opened her eyes and was able to follow commands. She then underwent surgery for her injury.
  • the patient was treated for cerebral infarction of the left internal capsule (verified by MRI scan) of 3 months duration using 10% FDP and 28% DMSO solution as described above. Prior to treatment, the patient could not move the fingers of the right hand or raise the partially paralyzed right arm above the horizontal plane. On the third day of treatment, the patient was able to partially move the fingers of the right and raise her right arm above her head.
  • compositions containing dimethyl sulfoxide and fructose 1,6-diphosphate may be administered parenterally (including intravenously, intramuscularly, intrathecally and subcutaneously),and topically, including to the mucosa or skin, (for example, sublingually and by inhalation) or by mouth.
  • Compositions administered for contact with the mucosa or skin result in systemic effects.
  • DMSO:FDP compositions may be administered as retention enemas or in the form of suppositories.
  • a pre-weighted vial of trisodium salt of fructose 1,6-diphosphate is dissolved by agitation in D5W (Dextrose 5% in water) to make up a final solution of 10% FDP.
  • D5W Dextrose 5% in water
  • a measured volume of 100% sterile, pyrogen free pharmaceutical grade DMSO is added to the FDP in D5W to make up a final solution of 28% DMSO.
  • the DMSO:FDP mixture in D5W will remain stable for several days at room temperature and for several weeks at 4°C. It is recommended that the DMSO:FDP solution be used soon after its preparation.
  • a patch composed of trilaminate of an adhesive matrix sandwiched between a non-permeable backing and a protective covering layer is prepared in the following manner:
  • a pressure-sensitive silicone adhesive composition such as BIOPSATM Q7-2920 (Dow Corning Corp., Midland, Michigan, U.S.A.) in DMSO (50% w/v) is added sufficient saturated solution of fructose 1,6-diphosphate in D5W to provide 10 mg fructose 1,6-diphosphate per ml.
  • the adhesive is applied to a polyester film in successive layers to provide about 5 mg of FDP cm 2 .
  • the film containing the adhesive is then made into patches of 10 cm 2 . Patches would be covered with a protective layer to be removed before application of the patch.
  • Tin DMSO is a permeation enhancer, there is no need to provide other permeation enhancers in making the patches.
  • compositions of the of the invention can also be used for donor organ preservation. It is well known that in the absence of oxygen, ATP breaks down rapidly. After twenty four hours, ATP loss is about 90% from liver, kidney and heart tissue. It is believed that as a consequence of the ATP loss, alteration in the activities of the enzyme systems occurs. Such alteration leads to eventual irreversible organ injury. DMSO protects donor organs prior to transplantation. FDP increases tissue levels of endogenous ATP. These agents in combination produce better viability and preservation of the donor organ.
  • FDP Fructose 1,6-diphosphate
  • the salt of the fructose 1,6-diphosphate may be used in preparation of the compositions of the invention. Dosage for administration of DMSO to animals would vary from about 10 mg/Kg to 1500 mg/Kg while dosage of FDP would be about 1 mg/Kg to 600 mg/Kg.
  • the active agents may be administered in any appropriate pharmaceutically acceptable carrier. Examples of such carriers are 5% dextrose, Ringer's lactate solution, or normal physiological saline.
  • the FDP could be provided as a saturated solution in a suppository form for administration in conjunction with DMSO.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Toxicology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (12)

  1. Zusammensetzung, welche neuronal schützend wirkende Mengen an Dimethylsulfoxid und Fructose-1,6-diphosphat oder ein pharmazeutisch verträgliches Salz davon und einen pharmazeutisch verträglichen Träger enthält.
  2. Zusammensetzung nach Anspruch 1, worin das Fructose-1,6-diphosphat in der Zusammensetzung als ein Salz vorliegt.
  3. Zusammensetzung nach Anspruch 1 oder Anspruch 2, wobei die Zusammensetzung 50 bis 1500 mg Dimethylsulfoxid und 1 bis 600 mg Fructose-1,6-diphosphat enthält.
  4. Zusammensetzung nach einem der vorangegangenen Ansprüche, worin der pharmazeutisch verträgliche Träger Dextrose ist.
  5. Zusammensetzung nach einem der vorangegangenen Ansprüche, worin der pharmazeutisch verträgliche Träger eine isotonische Lösung ist.
  6. Zusammensetzung nach einem der vorangegangenen Ansprüche, wobei die Zusammensetzung als ein Pflaster konfektioniert ist.
  7. Zusammensetzung nach einem der Ansprüche 1 bis 5, wobei die Zusammensetzung für rektale Verabreichung geeignet ist.
  8. Zusammensetzung nach einem der Ansprüche 1 bis 5, wobei die Zusammensetzung für intravenöse Verabreichung geeignet ist.
  9. Zusammensetzung nach einem der vorangegangenen Ansprüche zur Verwendung als ein Arzneimittel.
  10. Zusammensetzung nach einem der vorangegangenen Ansprüche zur Verwendung als ein neuronal schützend wirkendes Arzneimittel.
  11. Verwendung einer Zusammensetzung nach einem der Ansprüche 1 bis 8 zur Herstellung eines Arzneimittels zum neuronalen Schutz.
  12. Verwendung einer Zusammensetzung nach einem der Ansprüche 1 bis 8 zur Herstellung eines Arzneimittels zur Verhinderung der Abreicherung von ATP.
EP94925157A 1993-07-30 1994-07-29 Medikament zum schutz vor neurologischen schäden Expired - Lifetime EP0711134B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US9935793A 1993-07-30 1993-07-30
US99357 1993-07-30
PCT/US1994/008669 WO1995003753A1 (en) 1993-07-30 1994-07-29 Medicinal for protection from neurological damage

Publications (3)

Publication Number Publication Date
EP0711134A1 EP0711134A1 (de) 1996-05-15
EP0711134A4 EP0711134A4 (de) 1998-07-29
EP0711134B1 true EP0711134B1 (de) 2000-09-06

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EP94925157A Expired - Lifetime EP0711134B1 (de) 1993-07-30 1994-07-29 Medikament zum schutz vor neurologischen schäden

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US (1) US5516526A (de)
EP (1) EP0711134B1 (de)
JP (1) JP3581150B2 (de)
AT (1) ATE196087T1 (de)
CA (1) CA2168203C (de)
DE (1) DE69425826T2 (de)
WO (1) WO1995003753A1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8440001B2 (en) 2005-09-12 2013-05-14 Abela Pharmaceuticals, Inc. Systems for removing dimethyl sulfoxide (DMSO) or related compounds, or odors associated with same

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0313696A1 (de) * 1987-10-28 1989-05-03 Mobil Oil Corporation Polynitratester und stabilisierende Wirkstoffe enthaltender Dieselbrennstoff mit verbesserter Cetanzahl
ATE196087T1 (de) * 1993-07-30 2000-09-15 Torre Jack De Medikament zum schutz vor neurologischen schäden
EP0982033A3 (de) * 1996-05-08 2000-06-07 Cypros Pharmaceutical Corporation Verwendung von Fructose-1,6-Diphosphat (FDP) zur Herstellung eines Medikamentes
US5731291A (en) * 1996-05-08 1998-03-24 Cypros Pharmaceutical Corp. Partially lyophilized fructose-1,6-diphosphate (FDP) for injection into humans
US6076528A (en) * 1996-05-09 2000-06-20 Cypros Pharmaceutical Corp. Injection of fructose-1,6-diphosphate (FDP) prior to coronary artery bypass grafting surgery
US5944020A (en) * 1997-02-25 1999-08-31 Cypros Pharmaceutical Corp. Use of fructose-1 6-diphosphate as an inotrope drug after cardiopulmonary bypass surgery
US5858985A (en) * 1997-10-03 1999-01-12 Markov; Angel K. Treatment of asthma with fructose-1,6-diphosphate
US6323190B1 (en) * 1998-07-31 2001-11-27 The Univeristy Of Georgia Research Foundation, Inc. Estrogen mimetics lacking reproductive tract effects
WO2000021543A1 (en) * 1998-10-09 2000-04-20 Cytrx Corporation Method and composition for treating ischemia and sickle cell anemia
US6475514B1 (en) 1998-12-03 2002-11-05 Andrew Blitzer Athletic patch
US20040048376A1 (en) * 2000-04-10 2004-03-11 Benoit Chabot Methods for modulating splicing and/or alternative splicing, and for identifying alternatively spliced units in genes
US6585996B1 (en) 2002-03-13 2003-07-01 Westlake Laboratories, Inc. Lipid-soluble thiamine derivatives in the treatment of autism
US20060281822A1 (en) * 2005-04-20 2006-12-14 Cardinal Associates, Inc. Treatment and prevention of elevated homocysteine
EP1937286B1 (de) * 2005-09-12 2016-03-09 Abela Pharmaceuticals, Inc. Zusammensetzungen aus dimethylsulfoxid (dmso)
US8435224B2 (en) 2005-09-12 2013-05-07 Abela Pharmaceuticals, Inc. Materials for facilitating administration of dimethyl sulfoxide (DMSO) and related compounds
US8480797B2 (en) 2005-09-12 2013-07-09 Abela Pharmaceuticals, Inc. Activated carbon systems for facilitating use of dimethyl sulfoxide (DMSO) by removal of same, related compounds, or associated odors
BRPI0921494A2 (pt) * 2008-11-03 2018-10-30 Prad Reasearch And Development Ltd método de planejamento de uma operação de amostragem para uma formação subterrãnea, método de contolar uma operação de amostragem de formação subterrânea, método de controlar uma operação de perfuração para uma formação subterrãnea, e método de realizar uma amostragem durante a operação de perfuração.
AU2010313253B2 (en) 2009-10-30 2015-02-19 Abela Pharmaceuticals, Inc. Dimethyl sulfoxide (DMSO) and methylsulfonylmethane (MSM) formulations to treat osteoarthritis
US9682048B1 (en) 2010-10-12 2017-06-20 Gene S. Rosen Multi-component formulations for the treatment of cognitive decline including Alzheimer's disease
US10183053B1 (en) 2017-06-19 2019-01-22 Gene S. Rosen Multi-component formulations

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5143831A (en) * 1988-08-30 1992-09-01 G. D. Searle & Co. Fructose 1,6-diphosphate aldolase catalyzed steroselective synthesis of sugars
ATE196087T1 (de) * 1993-07-30 2000-09-15 Torre Jack De Medikament zum schutz vor neurologischen schäden

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8440001B2 (en) 2005-09-12 2013-05-14 Abela Pharmaceuticals, Inc. Systems for removing dimethyl sulfoxide (DMSO) or related compounds, or odors associated with same
US9186472B2 (en) 2005-09-12 2015-11-17 Abela Pharmaceuticals, Inc. Devices for removal of dimethyl sulfoxide (DMSO) or related compounds or associated odors and methods of using same

Also Published As

Publication number Publication date
EP0711134A1 (de) 1996-05-15
US5516526A (en) 1996-05-14
JPH09501163A (ja) 1997-02-04
JP3581150B2 (ja) 2004-10-27
CA2168203A1 (en) 1995-02-09
EP0711134A4 (de) 1998-07-29
WO1995003753A1 (en) 1995-02-09
CA2168203C (en) 2009-09-15
DE69425826D1 (de) 2000-10-12
DE69425826T2 (de) 2001-01-11
ATE196087T1 (de) 2000-09-15

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